JPS60199814A - Ubidecarenone fat emulsion - Google Patents

Abstract

PURPOSE:An oral administration pharmaceutical, containing ubidecarenone in a fat emulsion, having good absorbability in digestive tracts, capable of keeping a high concentration in blood, effective for improving various symptoms caused by cardiac failure, and useful as a cardiovascular pharmaceutical. CONSTITUTION:An oral administration pharmaceutical obtained by incorporating given amounts of a hydrophobic substance, e.g. vegetable oil or animal oil, with an emulsifying agent, e.g. phospholipid or nonionic surfactant, ubidecarenone and another additive, adding a required amount of water thereto, roughly emulsifying resultant mixture, and homogenizing the emulsion in an injection type high- pressure homogenizer, etc. The content of the ubidecarenone to be used is preferably 0.01-30mg/ml, particularly 0.05-20mg/ml. Administration in a high dose is not required, and development of side effects, e.g. uncomfortable feeling in the stomach part, inappetence, vomiting and diarshea, is prevented.

Description

[Detailed description of the invention] The present invention relates to ubiquitous non-fat emulsions.

Uvitehenone is Coenzyme Q+O or Ubiquinone 1
It is a quinoline derivative, also called 0, and is effective in improving hemodynamics in patients with heart failure, preventing deterioration of cardiac function, and improving dyspnea, wet cough, hepatomegaly, and edema associated with hemorrhagic heart failure.

Since Ubidecareno/ requires long-term administration to patients, it has traditionally been administered orally in the form of tablets for convenience of use. Only medium concentrations were obtained. For this reason, 1. W
Patients must be administered a much larger amount of Uvitecareno/f than originally required, but side effects on the gastrointestinal tract such as anterior discomfort 2, decreased appetite, nausea, and diarrhea have been observed. Ta.

As a result of intensive research aimed at solving these drawbacks, the present inventors have found that by incorporating ubidecarenone into a fat emulsion, its gastrointestinal absorption is improved, and the present invention has been completed.

An object of the present invention is to provide an orally administered preparation of ubidecarenone that has good absorption in the gastrointestinal tract and can maintain a high blood concentration.

The fat emulsion of the present invention is a fat emulsion containing ubidecarenone.

In the present invention, fat emulsion refers to 1 to 50% of hydrophobic substances (e.g., vegetable oils and animal oils) and 0.1 to 10% of emulsifiers (e.g., phospholipids, surfactants, etc.).
It consists primarily of water and a moderate amount of water. In addition, emulsifying aids (for example, an amount of 3 or less carbon atoms with a carbon number of 6 or less) may be added as necessary.
~22. Preferably, 12 to 20 fats or physiologically acceptable salts thereof), stabilizers (for example, 05
λ% or less, preferably 01'/, pre-emptive amount of cholesterol or 5Z% or less, preferably 1z% or more of 1jY phosphatidine 3) may also be added, depending on the use. Isotonic agents (e.g., glycerin, glucose, etc.) and pH adjusters (e.g., hydrochloric acid, sodium hydroxide, etc.) can also be used.
゜The content of ubidecarenone in the fat emulsion of the present invention is 00
1~3omg7me, preferably 005~207nW
/ml, and can be increased or decreased as appropriate depending on the form of the emulsion and its use, but it is usually 01 to 10 my/ml and 1 min. .

The degree of purification of the hydrophobic substances, emulsifiers, emulsification aids, and other additives used herein is not particularly limited as long as they can be used for pharmaceutical purposes.

Vegetable oils that can be used as hydrophobic substances include soybean oil, coma oil,
Olive oil, etc., and animal oils include eicosabe/tae heptaic acid, etc.

These include Ringetsu Teiga and &:i, υ141 Kushi/Chin, and Oeshi/Chin.

Further, the surfactant is mainly a nonionic surfactant, such as polyalkylenoglycol (for example, an average molecular weight of 1000 to +0000, preferably 4000 to +0000).
6,000 polyethylene glycol), polyoxyalkylene copolymers (e.g., average molecular weight 1,000 to 20
000. 6,000 to +0,000 polyoxyethylene-polyoxypropylene copolymer), hydrogenated human oil polyoxy7-alkylene derivatives (for example, hydrogenated human oil polyoxyethylene-(20)-ether, the same (
40)-ether, same (100)-ether),
Castor/oil polyoxyalkylene/derivatives (e.g. castor/oil polyoxyethylene-(20)-ether, same (
40)-ether, same (+00)-ether, etc.) can be used.

Anionic surfactants such as cholic acid can also be used.

Any fatty acids having 6 to 22 carbon atoms that can be added to pharmaceuticals can be used as emulsification aids. This fatty acid may be linear or branched, but stearic acid, oleic acid, and linoleic acid are ll'J-chain.

Valmitic acid, lylunic acid, myristic acid, etc. are preferably used. These salts include physiologically acceptable salts, such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (cal/lamb salts, etc.). salt, etc.) can be used.

The fat emulsion of the present invention can be produced, for example, by the following method.

i.e., the amount of hydrophobes, emulsifiers, ubidecareno/
and other additives, etc. are mixed and heated (1), then the required amount of water is added, and the mixture is coarsely emulsified using a homomixer.

Next, further homogenization was performed using a jet-type high-pressure homogenizer.
A fat emulsion of the present invention is obtained.

Depending on manufacturing circumstances, pi 1 may be added after preparing the fat emulsion.
A conditioning agent or the like may be added.

Kishomei's fat emulsion can be administered orally, and is administered as ubidecarenone at 10 to 10 fl+y (z) divided into 6 times a day after meals.

The fat emulsion of the present invention has fat particles with an average particle diameter of 10 μm.
Because it is extremely fine, it not only has good storage stability but also excellent gastrointestinal absorption. Therefore, its action is rapid and stable, and the dosage can be reduced, thereby suppressing the occurrence of side effects.

As described above, the fat emulsion of the present invention is effective in improving various symptoms caused by heart failure and is useful as a cardiovascular agent.

The present invention will be specifically explained below with reference to Examples and Test Examples.

Example 1 Egg yolk renotin 362 and ubidecarenone 0181 were added to purified soybean oil 601 and dissolved by heating.

This and 200m7 of distilled water! Then, Japanese Pharmacopoeia glycerin 7, 59 was added, the total amount was adjusted to 300-300 with distilled water, and the mixture was roughly emulsified using a homomixer. Using a Manton-Gorlin type homogenizer, the secondary pressure was 50 Kg/c.
emulsification by passing the mixture 20 times under a total pressure of 500 Ky/c4. This resulted in a homogenized fat emulsion containing extremely fine ubidecarenone. The average grain size of this emulsion was 02 to 04 microns.

Example 2 Ubidecarenone (52) was added to Olympus 507 and dissolved by heating. To this, all 62 egg yolk syntins were added and dissolved by heating, then purified water was added to make up 500 ml, and the mixture was emulsified for 15 minutes using a homomixer to obtain a rough emulsion. This liquid was emulsified using a Manton-Gorlin homogenizer (2
Next pressure + D D K? /cn1. Total pressure -8 s s o Ky/cnt) shi, kiwa methi la, a
Fat emulsion containing %/y f
Manufactured. The average grain size of this emulsion was f10.2-04μ.

Example 5 Ubidecarenone 061 was added to 100 liters of soybean oil and dissolved by heating. Add this in advance to vIJ yellow lecithin 601.
The mixture was stirred and suspended in 350ml of heated purified water, and further purified water was added to bring the total volume to 500ml.

This liquid was emulsified using a Manton-Gorlin homogenizer in the same manner as in Example 1 to prepare a fat emulsion containing ubidecarenone. The average grain size of this emulsion was 0.2-04μ.

Test Example 1 A group of 6 female peagle dogs weighing 9 to 14 kg were subjected to the test.

A Uvitecareno/Ryokud fat emulsion was prepared according to Example 1,
This was orally administered as ubidecarenone to one group of animals at a rate of 20 mlt/dog, 6 times on day +, for 12 days.

To another group of animals, tablets containing 10 to 10 ubidecarenone were orally administered in the same manner as the fat emulsion so that the amount of ubidecarenone was the same as that of the fat emulsion. Blood was collected once a day from the forearm vein of the animal, and subjected to HPL using a separation column backed with Nucleonle sL+g t-back.
C, and the changes over time in the blood concentration of ubidecarenone were investigated.

The results are shown in FIG.

As is clear from FIG. 1, the fat emulsion of the present invention exhibited approximately twice the blood concentration as compared to the tablet.

Test Example 2 The ubidecarenone fat emulsion prepared in Example 1 was orally administered to rats.

30 m as ubidecarenone, which is considered to be the maximum dose volume.
Since no deaths were observed even after administration of y/Kg, LD5o was estimated to be 30 my/Kg or more.

[Brief explanation of drawings]

FIG. 1 shows the time course of the blood concentration of ubidecarenone when the fat emulsion or tablet containing ubidecarenone of the present invention was orally administered to test animals. In the figure, A shows the curve of the fat emulsion and B shows the curve of the tablet. %W1; Applicant Taisho Pharmaceutical Co., Ltd. Agent NoP Tomi Kitagawa] Diagram time (dELy) Procedural amendment (spontaneous, method) July 19, 1980 Commissioner of the Japan Patent Office 2 Name of the invention ubitecarenone fat Relationship with tenant farmers who correct emulsion 5 sleeves Patent applicant address: 1'IT, 3-24-1 Takada, Toshima-ku, Tokyo
Taisho Pharmaceutical Co., Ltd., 5-24-1 Takada, Toshima-ku, Tokyo 171 Internal Specification 6 Contents of amendment (1) Printing of specification (no change in content) List of Z attachments (1) Full text amended specification 1 letter

Claims (1)

[Claims] 1) Fat emulsion containing ubidecarenone.